PROJECT SUMMARY/ABSTRACT Why the brain continues to undergo functional and histopathological decline after a traumatic injury is a central question in the field of traumatic brain injury (TBI) research, and the answer has important implications for the development of effective therapies. Despite the fact that TBI is a highly heterogeneous group of clinical brain disorders, inflammation is observed in nearly all injuries and it is likely the key driver of long-term decline and degeneration. This notion is supported by increasing evidence from classical degenerative diseases like Alzheimer?s disease indicating a role for astrocytes and microglia in promoting long-term inflammation. In early TBI, these cells have a supportive role in recovery but over time, their continued activation likely contributes to inflammation and decline although our mechanistic understanding remains limited. In part, the foundational work in the field of TBI research predates the advent of unbiased sequencing techniques; thus, the application of these technologies to the study of TBI could reveal entirely novel genes and processes central to its pathogenesis. Our lab recently developed a head-directed injury model of TBI in Drosophila, resulting in an injury phenotype that captures the key features of mammalian disease including temporary loss of consciousness, learning and memory impairments, brain degeneration and mortality. Results from a time course RNA-sequencing study using our TBI model highlights the oncogenic transcription factor Ets21c as a key player throughout injury response, based on its significant and persistent upregulation post-injury. Though Ets21c expression is minimal at baseline, preliminary data confirms Ets21c is highly expressed in glia after injury. Results from a pilot study show that Ets21c knockdown rescues survival post-TBI, suggesting a specific role for Ets21c in regulating the pathogenic functions of glia. Thus, this application examines a novel role for Ets21c in TBI, with the hypothesis that Ets21c drives long-term glial reprogramming to promote brain inflammation and decline after TBI. The goal of this proposal is to elucidate the role of Ets21c in traumatic injury by 1) characterizing Ets21c expression following traumatic brain injury, 2) determining the functional, molecular and cellular consequences of Ets21c knockdown in TBI and 3) defining the glia- specific transcriptional role of Ets21c in TBI pathogenesis. These studies will expand our understanding of transcriptional reprogramming in glial in injury settings and provide a detailed molecular mechanism for further study in higher animal models.